Trans-resveratrol is a polyphenol enriched in red wine, grape skin and Japanese knotweed (Polygonum cuspidatum Sieb. & Zucc.). Trans-resveratrol's anticancer properties have been demonstrated in cell culture and animal studies. These studies suggest that there is a dose response effect. There is convincing preclinical evidence that botanicals alter the methylation status of critical genes, leading to the downregulation of cell proliferation. Our hypothesis is that trans-resveratrol alters the methylation pattern of multiple genes, including tumor suppressor and tumor promoting genes, leading to a decrease in cell proliferation and other changes which decrease a woman's chance of developing breast cancer. In this randomized, double blind, placebo controlled translational study, for 12 weeks high risk women will twice daily take a preparation of P. cuspidatum containing either placebo, 5 mg or 50 mg of trans-resveratrol. The doses chosen were based upon concentrations commonly available and recommended in dietary supplements, and allow us to determine if there is a dose response. We will perform mammary ductoscopy (MD), a minimally invasive procedure which we have performed in over 400 women without complication, to collect a concentrated sample of breast ductal epithelial cells. In addition to collecting MD samples for cellular studies, nipple aspirate fluid (NAF) will be collected to measure extracellular levels of breast specific compounds. In Aim 1 we investigate the effects of trans-resveratrol on gene methylation and cell proliferation. Aim 2 will investigate the concentrations of free trans- and cis-resveratrol, as well as conjugated trans-resveratrol, in NAF and serum after long term oral intake. Aim 2 will also allow us to assess compliance with the study agent. This study will provide human data on 1) the effects of trans-resveratrol on methylation and cell proliferation, and 2) trans-resveratrol systemic and breast specific levels after long term low and high dose ingestion of the agent. The role that nutraceuticals and diet play in preventing cancer is an emerging field of study, and there is growing evidence that compounds in our diet, i.e., green tea extract and soy isoflavones, work by suppressing tumor promoting and/or by turning on tumor suppressor proteins. This study will examine trans-resveratrol's effects on gene expression and the production of suppressor proteins to see if it will favorably protect cells from cancer in high risk women. As more and more Americans turn to nutraceuticals for a healthier lifestyle, studies like these are increasingly important in the fight against cancer. [unreadable] [unreadable] [unreadable]